Identification of transcriptomic responses related to normal, healthy and accelerated aging

Abstract

Aging is defined as the reduction in the physiological and adaptive capabilities of organisms with the passage of time. The accumulation of DNA damage could be the central event on which other factors related to the aging process coalesce. One of the links connecting DNA damage to aging are the progeroid syndromes caused by a deficiency of DNA transcription-coupled nucleotide excision repair (TCR-NER) subpathway. There is a parallel between the transcriptional response of progeroid mice and mice on a dietary restriction (DR) regimen (an intervention that extend the lifespan). DR increased resistance to different forms of acute stress. Corroborating that TCR-NER deficiency induces activation of similar protective mechanisms, Csb-/- and Csa-/- mice are less susceptible to renal ischemia-reperfusion injury. The parallel between the transcriptomic responses of animals at two life expectancy extremes, in addition to the shared increase in resistance to ischemia-reperfusion injury, has been explained by the existence of a programmed survival response. This thesis addresses several questions related with the survival response, the mechanism of neurodegeneration and normal aging using mainly analysis of transcriptomic data. First, it was established that old mice activate an incomplete survival response after three days of DR, second, a common mechanism of activation of the protective response was described. Third, a connection between the accumulation of DNA damage and neurodegeneration was provided. Finally, an integrative methodology of analysis was used over brain human transcriptomic data, the result was the identification of an opposite activation of astrocytes in the human aged prefrontal cortex.